tbuckley/cabot-search huggingface dataset:
PB1852: AZACITIDINE COMBINED WITH HAG REGIMEN FOR ELDERLY PATIENTS WITH ACUTE MYELOID LEUKEMIA:PRIMARY ANALYSIS OF A RETROSPECTIVE COHORT
Authors: W. Zheng, S. CUI, J. Wang, Y. Wang, J. Xu, Y. Zhou, Z. Liu, R. Xu
Journal: HemaSphere (2022)

Background: Retrospective analysis of azacytidine combined with HAG regimen in elderly patients with acute myeloid leukemia Aims: To investigate the clinical efficacy and safety of azacytidine combined with HAG regimen in the treatment of senile acute myeloid leukemia. Methods: 21 elderly patients with acute myeloid leukemia (AML) hospitalized in The Affiliated Hospital of Shandong University of Traditional Chinese Medicine from January 2019 to January 2022 were retrospectively analyzed, including 10 males and 11 females, with a median age of 67 years (60-75 years).Among them, 14 patients were newly treated and 7 patients were relapsed and refractory. Among the newly treated patients, 6 patients were in the poor prognosis group, 6 patients were in the moderate prognosis group and 2 patients were in the good prognosis group. Treated with Azacitidine combined with HAG regimen (azacytidine 75mg/(m2·d), iH D1-7+ homoharringtonine 1mg/(m2·d) D2-8+ cytarabine 10mg/m2 iH, D2-8+ G-CSF 200ug / (m2·d) iH D1-8). and observed the complete response rate (CR), total response rate (ORR) and the occurrence of adverse reactions in 21 patients,after 1 course of induction chemotherapy. Results: The total effective rate (ORR) and complete response rate (CR) of azacitidine combined with HAG regimen in the treatment of elderly acute myeloid leukemia were 85.7% and 61.9% respectively.For the newly treated patients, The ORR was 78.57%, and the CR rate was 64.29% (9/14). For the recurrence refractory patients, the ORR was 100%, but the CR rate was low, accounting for 28.57%.Among the newly treated patients, the CR rates of the good prognosis group, the medium prognosis group and the poor prognosis group were 100%, 66.67% and 50%, respectively, and the differences were statistically significant.The main adverse reactions during the treatment were myelosuppression, of which the incidence of grade 3-4 myelosuppression was 21.43% in newly treated patients and 28.57% in refractory patients.One patient died early in the initial treatment, due to infection in the myelosuppression stage, which induced heart failure. Summary/Conclusion: Azacitidine combined with HAG regimen is effective in the treatment of acute myeloid leukemia (AML) with early treatment in elderly patients and refractory relapse, with few adverse reactions and good tolerability.
P806: IMPACT OF MARROW HEMOPHAGOCYTOSIS IN DIAGNOSTIC DEFINITION AND PROGNOSTIC SIGNIFICANCE IN ADULT POPULATION
Authors: C. Almeida, T. Cardoso, A. Roque, S. Moreira, J. Cascais Costa, N. Silva, L. Santos, C. Geraldes
Journal: HemaSphere (2022)

Background: Hemophagocytic lymphohistiocytosis (HLH) is associated with high mortality and is an entity difficult to diagnose. Bone marrow hemophagocytosis (BMHF) is the most easily accessible histomorphological criterion, but per si is neither specific nor sensitive for the diagnosis of HLH and its clinical significance is still not clear, mainly in adult population Aims: To evaluate the clinical and prognostic significance of BMHF. Methods: Retrospective analysis of adult patients with documentation of BMHF between 2007 and 2020. The identification of the patients was carried out by searching the database by the following keywords: “phagocytosis”, “phagocyte” and “histiocyte”. For the definition of HLH, the HLH-2004 and the revised HLH-2009 criteria were applied. HScore values ​​>169 were considered highly suggestive of HLH. Stratified models for each of the risk scores (HLH-2004 and HLH-2009) were compared using Akaike’s information criterion (AIC) and the Harrell’s concordance index (C-index). Results: Ninety-five patients (pts) were included, 63.2% males with median age of 64 (20-95) years old. Twenty-two pts (23.2%) presented ≥5 HLH-2004 criteria and 24 (25.3%) HLH-2009 criteria, with only 6 patients (27.3%) with simultaneous diagnosis by both criteria (Cohen’s kappa 0.0253). Forty-three (45.3%) patients presented ≥3 HLH-2004 criteria and 34 pts (35.8%) had Hscore>169. After a median follow-up of 24.3 months, the median overall survival (OS) was 39.4 months. OS was significantly lower in patients with ≥5 HLH-2004 (0.9 vs 86.5 M; HR 3.56; p<0.001), with ≥3 HLH-2004 criteria (3.17 vs NR; HR 2.95; p<0.001), with HLH-2009 criteria (5.5 vs 78.0 M; HR 1.89; p=0.034), and HScore>169 (1.45 vs 86.5; HR 3.08; p<0.001), compared with those that do not have. Excluding variables included in the above scores, the only clinical/analytical variable that was statistically significant for OS in univariate analysis was LDH>UNL (HR 1.02; p<0.001). After multivariate analysis for age, aetiology and LDH>ULN, ≥5 HLH-2004 (HR 4. p<0.001), HLH-2009 2009 (HR 1.87 p=0.045), ≥3 HLH-2004 (HR 3.06; p<0.001) and Hscore>169 (HR 3.39; p=0.001), the four scores retain significance for OS. In patients with BMHF, HLH-2004 criteria discriminated best between patients with poor and favourable OS than HLH-2009 (C-index 0.6364 vs 0.5601; AIC 400.24 vs 411.53). Concerning the aetiology, 51.6% was neoplastic (24.5% [n=12] with ≥5 HLH-2004 criteria), 13.7% infectious, 28.4% autoimmune and in 28,4% the trigger was not identified. Summary/Conclusion: In our cohort, HLH-2004 criteria had the best predictive value for OS, compared with HLH-2009 However, in the absence of the data need to calculate these scores, both ≥3 HLH-2004 criteria and Hscore>169 are independent predictors of OS, which, due to the deleterious prognosis of HLH, support their utility to start treatment earlier
PB2337: BURDEN OF HOSPITALIZATION, COSTS AND CO-MORBIDITIES IN MEDICAID PATIENTS WITH VENO-OCCLUSIVE DISEASE (VOD): ANALYSIS OF NATIONAL IN-PATIENT HOSPITAL DATABASE
Authors: S. Aggarwal, S. Kumar, A. Bela, O. Topaloglu
Journal: HemaSphere (2022)

Background: Veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT) conditioning or high-dose nontransplant chemotherapy. Aims: To analyze trends in hospital length of stay, total costs and co-morbidities in Medicaid patients with Veno-Occlusive Disease (VOD) Methods: The National Inpatient Sample (NIS) data set from the Healthcare Cost and Utilization Project was utilized in order to determine the number of hospital admissions for VOD. Thirty co-morbidities were assessed using Elixhauser scoring. Results: There were an estimated 190 hospitalizations with a diagnosis of VOD, with 50% of the patients being covered by Medicaid. The mean age was 15 (SD 16.03) years and 58% of the patients were female. The mean hospital length of stay for Medicaid patients with VOD was 53.47 (SD 40.17) days (Median was 48 days). The mean hospital charges were $1,541,016 (SD $1487179). The mean comorbidity score was 3.53 (SD 1.54). The in-hospital mortality rate was 15.79%. The vast majority of the patients were Hispanic (58%), followed by Asian (16%), Black (11%) and White (11%). The top five listed diagnoses were Liver Disease (100%), Fluid and Electrolyte Disorders (68%), Coagulopathy (47%), Cardiac Arrhythmias (21%) and Hypertension (5%). The top 3 procedure codes were for stem cell transplant, ventilation and bone marrow extraction. Summary/Conclusion: High hospital burden of VOD in Medicaid patients shows there is a need for better treatment management for these patients.
PB2008: CUTANEOUS HEMORRHAGIC SYNDROME IN PATIENTS WITH AL-AMYLOIDOSIS
Authors: V. Khyshova, I. Rekhtina, N. Zozulia, V. Dvirnyk, L. Mendeleeva
Journal: HemaSphere (2022)

Background: Hemorrhages on the skin and mucosa are seen in 30-40% of patients with systemic AL amyloidosis (AL-A). The pathogenesis and clinical significance of this syndrome are poorly understood. Aims: To analyze the relationship of cutaneous and mucous hemorrhagic syndrome in AL-A patients with the hemostatic system parameters and the leading clinical syndromes. Methods: A prospective study included 49 patients with newly diagnosed systemic AL-A. 18 (37%) patients were diagnosed with stage I, 16 (33%) with stage II, and 6 (12%) and 9 (18%) with stage III and stage IV, respectively (Mayo 2004/Europian). Activated partial thromboplastin time, thrombin time, fibrinogen concentration, XIIa-dependent fibrinolysis time, antithrombin III (ATIII), D-dimer, factors VIII (FVIII), X (FX) and Von Willebrand factor (VWF) activity were determined before therapy. Patients with cutaneous hemorrhagic syndrome were included in the Group №1, and those without cutaneous hemorrhages in the Group №2. Results: Cutaneous and mucosal hemorrhagic syndrome was observed in 23 (47%) patients. Hypercoagulable syndrome (increase of fibrinogen, D-dimer, FVIII, VWF, and decrease of ATIII) was registered in 18 (78%) patients, significantly more frequently than in Group №2 patients (11 patients - 42%; p=0,01). Eight (35%) patients with skin hemorrhages developed venous and arterial thrombosis before treatment, which were absent in the control group (p=0.002). Nephrotic syndrome was present in 19 (82%) group №1 patients, nephrotic syndrome was 2 times less frequent in group №2 (10 (38%) patients, p=0,001). Patients with hemorrhages had higher urinary protein loss (5.7 g/day vs 2.4 g/day; p=0.03) and lower serum albumin values (23 g/l vs 33 g/l; p=0.001). In patients from the first group, the development of hydropericardium, hydrothorax and anasarca was more often observed (p=0.02). We didn’t find significant correlation between cutaneous hemorrhagic syndrome and involvement of other organs, content of free light chains and cardiac markers. Summary/Conclusion: Cutaneous hemorrhagic syndrome is a clinical manifestation of hypercoagulable disorders in the hemostasis system in AL-A patients and associated with a high frequency of thrombosis development. Skin hemorrhages were more often associated with severe nephrotic syndrome, which may indicate a single pathogenetic mechanism in the form of small vessel lesions.
PB1961: ZNO NANOPARTICLES INDUCE MULTIPLE MYELOMA CELL DEATH BASED ON REACTIVE OXYGEN SPECIES AND CASPASE SIGNALING PATHWAY
Authors: Z. Li, X. Yin, C. Lyu, S. Cui, J. Wang, Y. Si, R. Xu
Journal: HemaSphere (2022)

Background: Human multiple myeloma (MM) is a malignant and incurable B cell tumor. Zinc oxide nanoparticles (ZnO NPs) have been widely used in biomedical fields including anti-bacterial and anti-tumor. However, the influence of ZnO NPs on MM cells is still unclear. Aims: The present study aimed to investigate the effect of ZnO NPs on MM cell (a human myeloma-derived RPMI8226 cell line) death in vitro and the underlying mechanism. Methods: The morphology of ZnO NPs was characterized by transmission electron microscopy (TEM), and the inhibitory and apoptotic effect of ZnO NPs on human MM cells was monitored by a CCK-8 method and an Annexin V-FITC/PI assay. Meanwhile, the morphological change in the cells after exposure to ZnO NPs was observed by a light field microscope. Moreover, the effects of ZnO NPs on the ATP level, reactive oxygen species (ROS) generation, and apoptosis were separately explored by the DCFH-DA fluorescent probe, flow cytometry, and ATP bioluminescence assay. Moreover, the expression of cytochrome C (Cyt-C), Apaf-1, Caspase-9 and Caspase-3 at mRNA and protein levels was further determined by using quantitative PCR (Q-PCR) and western blotting. In the present study, the human peripheral blood mononuclear cells (PBMCs) were used as normal control samples for the relevant experiment. Results: The results indicated that ZnO NPs could significantly inhibit human MM cell proliferation and cell death in a time- and dose-dependent manner in vitro, and this outcome can be confirmed by cell morphology and apoptosis assay. Meanwhile, the results also showed that ZnO NPs could effectively increase ROS production and decrease ATP levels in human MM cells. ZnO NPs could also significantly elevate the expression of Cyt-C, Apaf-1, Caspase-9 and Caspase-3 at mRNA and protein levels, leading to cell death. By contrast, ZnO NPs showed little cytotoxic influence on PBMCs. Image:Summary/Conclusion: ZnO NPs can significantly induce human MM cell death in a time- and dose-dependent manner in vitro, decrease the ATP production and enhance the ROS generation. ZnO NPs can also increase Cyt-C, Apaf-1, Caspase-9 and Caspase-3 expression at mRNA and protein levels in human MM cells, and initiate MM cell apoptosis, indicating that Cyt-C, Apaf-1, Caspase-9 and Caspase-3 play crucial roles in ZnO NPs-induced, mitochondria-mediated apoptosis in human MM cells. Overall, ZnO NPs may be a potential agent in treating human multiple myeloma in clinical practice.
P939: SYNERGISTIC EFFECTS OF LOW DOSE BELANTAMAB MAFODOTIN IN COMBINATION WITH A GAMMA-SECRETASE INHIBITOR (NIROGACESTAT) IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM): DREAMM-5 STUDY
Authors: A. Nooka, S. Lonial, S. Grosicki, M. Hus, K. Song, T. Facon, N. S. Callander, V. Ribrag, K. Uttervall, H. Quach, V. Vorobyev, C.-K. Min, S. Cheng, L. M. Smith, J. Yu, T. Collingwood, B. Holkova, B. E. Kremer, I. V. Gupta, P. G. Richardson, M. C. Minnema
Journal: HemaSphere (2022)

Background: Preclinical data demonstrate that nirogacestat, a gamma-secretase inhibitor, may increase cell-surface levels of a B-cell maturation antigen (BCMA) and reduce soluble BCMA levels, which could enhance anti-BCMA agent activity in multiple myeloma. In the DREAMM-5 (NCT04126200) Phase I/II platform trial belantamab mafodotin (belamaf; BLENREP), a BCMA-targeting antibody-drug conjugate, is being evaluated in combination with nirogacestat. Aims: The aim of this study is to determine if the combination can result in similar efficacy and an improved ocular safety profile compared to the currently approved belamaf schedule (single agent dose 2.5 mg/kg Q3W) in patients with RRMM which showed a 31% overall response rate (ORR) and 44.5% Gr3/4 keratopathy (BLENREP US prescribing information). Methods: This cohort within the DREAMM-5 nirogacestat combination sub-study has a sequential dose-exploration (DE) phase evaluating 0.95 mg/kg Q3W belamaf with 100 mg BID nirogacestat continuously, followed by a randomized cohort expansion (CE) comparing the combination to a belamaf 2.5 mg/kg Q3W arm. Results: Preliminary results from the 10 patients in the DE cohort with low-dose belamaf + nirogacestat, are presented in this abstract. Patients had a median (range) of 4.5 (3–10) prior lines of therapy. At time of data cut-off (Nov 15, 2021), patients received a median (range) of 7 cycles (1–26). The ORR was 60% (n=6/10) and 20% (n=2) achieved a very good partial response (Table). The key emergent adverse events (AEs) included ocular events (n=7 [70%]; ≥Grade [Gr] 3, n=2 [20%] of which Gr 3 keratopathy was reported in 1 patient [10%]), diarrhea (n=7 [70%]; Gr3, n=1 [10%]) and hypophosphatemia (n=7 [70%]; Gr3, n=1, [10%]). There were 2 Grade 5 AEs, neither of which were related to study treatment. No patient permanently discontinued study due to treatment related AEs. Image:Summary/Conclusion: Encouraging clinical activity and a manageable safety profile is observed with low dose belamaf (0.95 mg/kg Q3W) + nirogacestat (100 mg BID continuously) in patients with RRMM. This ongoing sub-study is actively recruiting patients and will continue to evaluate belamaf + nirogacestat efficacy and safety. Updated results will be reported at the congress. Funding Statement: GSK (208887); drug linker technology licensed from Seagen Inc.; mAb produced using POTELLIGENT Technology licensed from BioWa. This abstract was previously submitted to the American Society of Clinical Oncology (ASCO) Annual Meeting, June 3–7, 2022, and is submitted on behalf of the original authors with their permission. ©2022 American Society of Clinical Oncology, Inc. Reused with permission. All rights reserved.
P1552: A PHASE 2, OPEN-LABEL STUDY TO ASSESS SAFETY, TOLERABILITY, AND CLINICAL EFFECT OF ANX005 IN PATIENTS WITH WARM AUTOIMMUNE HEMOLYTIC ANEMIA AND EVIDENCE OF COMPLEMENT ACTIVATION
Authors: U. Jaeger, C. Broome, R. Go, A. Patriarca, A. Roeth, Q. Chang, N. Weedin, P. Adams, E. Cahir-McFarland, H.-A. Kroon
Journal: HemaSphere (2022)

Background: Autoimmune hemolytic anemia (AIHA) is caused by autoantibody destruction of red blood cells (RBCs) and is divided into warm autoimmune hemolytic anemia (wAIHA) and cold agglutinin disease. In wAIHA, which accounts for 60-70% of AIHA cases, polyclonal immunoglobulin G (IgG) antibodies cause hemolysis of RBCs at core body temperatures. However, approximately 50% of wAIHA cases are not caused by pathogenic IgG alone. The correlation between autoimmune hemolysis and presence of complement on RBCs in wAIHA patients suggests a role for the complement system in the pathogenesis of wAIHA, which can be triggered by C1q binding to autoantibodies bound to RBCs. ANX005 is a humanized IgG4 monoclonal antibody that selectively binds and inhibits C1q, blocking activation of the classical complement pathway, with the potential to inhibit complement-mediated hemolysis in wAIHA. Aims: The goal of this clinical study is to evaluate two once-weekly IV infusions of ANX005 in patients with wAIHA having evidence of complement pathway activation to understand the effect of C1q inhibition on pathway markers and objective disease parameters. Methods: This is an open-label, repeat-dose, Phase 2 study (NCT04691570) of ANX005 in patients with wAIHA and evidence of classical complement pathway activation. Up to 12 patients will be enrolled in this study and undergo a screening period of up to six weeks prior to Day 1. Patients will receive two doses of ANX005 on Days 1 and 8. Safety and pharmacokinetic (PK)/pharmacodynamic (PD) evaluations will be completed on Days 4, 15, 22, 29, 36, 43, 50, 57, and 71. Individual study duration will be up to 16 weeks, and patients will complete study participation on Day 71. The primary objective is to evaluate the safety and tolerability of ANX005. Secondary objectives include evaluating the PK and PD profile of ANX005, examining markers of classical pathway activation, and determining the impact of classical complement inhibition on hemoglobin levels and biomarkers of hemolysis through Day 71 in this subset of patients. Results: Results from the Phase 2 trial are expected by the end of 2022. Image:Summary/Conclusion: In this Phase 2 study of ANX005 in patients with wAIHA and evidence of classical complement pathway activation, patients will receive two IV doses of ANX005 one week apart with the goal of evaluating its safety, tolerability, PK/PD, and clinical effect to further understand the role of classical complement in this heterogeneous disease as a target for effective therapy.
PB1779: DEVELOPING NOVEL SYNERGISTIC DRUG COMBINATIONS WITH VENETOCLAX IN ACUTE MYELOID LEUKAEMIA
Authors: R. Harrigan, E. Johnston, K. Matchett, T. Bjourson
Journal: HemaSphere (2022)

Background: The treatment of AML remains a challenge due to complex genomic heterogeneity. In recent years, advancements in genomic technologies and the development of targeted therapies have changed the treatment paradigm, offering targeted treatments for patients with specific genomic vulnerabilities (1). The orally available BCL-2 inhibitor venetoclax is well tolerated and has recently received FDA approval in combination with hypomethylating agents (HMAs) for the treatment of newly diagnosed AML patients unfit for standard induction chemotherapy. Recent clinical trials have shown complete remission in around 70% of newly diagnosed AML cases with venetoclax and HMA regimens (2,3). However, relapses are common and there is still an unmet need for effective therapies with long-lasting remissions. The development of novel combinations allows for dual targeting of molecular drivers in AML. Recent studies have investigated novel venetoclax-based combination regimens to further improve anti-leukemia efficacy, evade drug resistance, reduce toxicities, and promote deep durable remissions. Venetoclax in combination with IDH1/2 inhibitors, FLT3 inhibitors, CDK inhibitors, and MEK inhibitors are among the most promising novel combination regimens currently being investigated (4–7). Aims: This investigation aims to develop novel synergistic drug combinations with venetoclax via high throughput screening of >2000 compounds to improve venetoclax safety, efficacy and overcome resistance. Methods: Venetoclax dose response experiments, Western blot analyses of BCL-2 protein expression and qPCR analyses of BCL2 gene expression were performe in a panel of 8 AML cell lines. A drug library comprised of 1,971 FDA approved compounds and 755 clinical compounds will be screened for anti-leukemia efficacy at 3 concentrations, in 3 AML cell lines at 3 timepoints. A secondary screen will combine successful candidate compounds with venetoclax and assess synergistic anti-leukaemic effect and ability to overcome resistance. Results: Venetoclax IC50 values in the 8 AML cell lines range from <0.01µM to >5µM highlighting differential response among the panel. Western blot and qPCR analyses showed diverse BCL-2 protein and BCL2 gene expression in the 8 cell lines which may account for variation in response. Summary/Conclusion: Further experiments will be performed to characterize mechanisms of induced cell death including target engagement analysis, Annexin V/ Propidium iodide staining. Candidate venetoclax-based combinations will be assessed for efficacy in a larger panel of cell lines and patient samples.
P969: COMPARISON OF VENOUS THROMBOEMBOLISM INCIDENCE IN MULTIPLE MYELOMA PATIENTS RECEIVING LENALIDOMIDE-BASED REGIMENS WITH RIVAROXABAN OR ASPIRIN THROMBOPROPHYLAXIS
Authors: Y. Wang, X. Tang, W. Zheng, Z. Wang, J. Xu, X. Tan, Y. Tian, R. Xu, S. Cui
Journal: HemaSphere (2022)

Background: Thromboprophylaxis is routinely used with lenalidomide-based regimens in multiple myeloma because of a substantial risk of venous thromboembolism (VTE). Aspirin is one of the most common thromboprophylaxis agent but also increases bleeding complications.Rivaroxaban represents a selective direct inhibitor of activated coagulation factor X (FXa) having peroral bioavailability and prompt onset of action which can mitigate the risk of higher incidence of VTE without an observable increase in bleeding rates.However, little is known about the incidence of VTE in lenalidomide-based regimens with rivaroxaban thromboprophylaxis. Aims: The purpose of our study was to compare of venous thromboembolism incidence in multiple myeloma patients receiving lenalidomide-based regimen with rivaroxaban or aspirin thromboprophylaxis. Methods: We conducted a single-centre retrospective study designed to assess the rates of VTE, including pulmonary embolism (PE) and deep vein thrombosis (DVT), in MM patients receiving lenalidomide-based regimen with aspirin or rivaroxaban thromboprophylaxis.A total of 130 patients who were not anticoagulated for other clinical indications and received at least 1 cycle of lenalidomide-based regimen between January 2015 and December 2021 were included. Clinical bleeding events after treatment were also important indicators in our study. Results: The incidence of venous thromboembolism in the rivaroxaban group was significantly lower than that in the aspirin prevention group (P<0.05). The incidence of bleeding in the rivaroxaban group was also lower than that in the aspirin prevention group,but there was no statistical significance(P﹥0.05). Table II. - Analysis of VTE and Bleeding. Regimen + prophylaxis R-based regimens+ASA（n=84） R-based regimens+XA（n=46） P-value VTE 13（15.5%） 1（2.2%） 0.041 Bleeding 6（7.1%） 0 0.081 ASA, aspirin; XA, rivaroxaban; VTE, venous thromboembolism. Image:Summary/Conclusion: In this pilot study, we found that rivaroxaban was safe and well-tolerated as the primary preventive measure for venous thromboembolism in patients with multiple myeloma receiving lenalidomide-based regimen. However, these findings warrant further investigation in a larger randomized study to be validated.